CLINICAL PRACTICE GUIDELINE FOR HEART
FAILURE DUE
TO LEFT-VENTRICULAR SYSTOLIC DYSFUNCTION
ENDORSED BY:
CHIEFS OF CARDIOLOGY
CHIEFS OF MEDICINE
UPDATE ON THE
PHARMACOLOGICAL MANAGEMENT OF HEART FAILURE
DUE TO LEFT-VENTRICULAR
SYSTOLIC DYSFUNCTION
INTRODUCTION
This is an
update of the
pharmacologic therapy for heart
failure due to left-ventricular systolic dysfunction. It incorporates
the
results of clinical trials that have been published since the May 1997
release of the Clinical Practice Guideline for Heart Failure due to
Left-Ventricular
Systolic Dysfunction. New information is covered in this document on
the
following pharmacologic therapies: ACE inhibitors;
alternatives to ACE
inhibitors, losartan and hydralazine-isosorbide dinitrate; beta-blockers;
spironolactone; inotropes; antiarrhythmics;
nonsteroidal anti-inflammatory drugs (NSAIDS); and other blood pressure
lowering drugs. Refer to the medication table ("Medications
Used
in
Heart Failure", page 3) and algorithm outlining "Pharmaceutical
Management
of Patients with Heart Failure Due to Left-Ventricular Systolic
Dysfunction"
in this update. The medication table and algorithm are also available
on
an updated pocket card.
The
information and
recommendations about the use of diuretics,
digoxin, anticoagulants and calcium channel blockers has not changed
since
the original guideline was published. It is summarized in this update
in
the medication table (page 3) and is contained on the pocket card. For
more detailed information on these medications refer to the May 1997
guideline.
The May 1997 guideline also includes information about other important
aspects of management of heart failure, such as
patient education, diagnostic
evaluation, and non-pharmacologic
therapies (revascularization, heart transplantation).
CARE MANAGEMENT
Recent observational studies
suggest that heart failure
care management programs can reduce hospitalization. These programs may
include patient education, medication titration, and frequent
monitoring.
Heart failure care management programs are available in all of our
service
areas.
ACE
INHIBITORS
Because
ACE
inhibitors (ACEI) improve survival and symptoms,
they remain the first line of therapy for patients with
left-ventricular
systolic dysfunction. They should be prescribed for all patients with
left-ventricular
systolic dysfunction unless specific contraindications exist. Recent
evidence
has shown that higher doses result in greater improvement in survival
and
fewer hospitalizations. Therefore, ACEI should be titrated toward the
maximum
dose until the highest tolerated dose is reached (maximum doses:
lisinopril
40 mg po qd, captopril 100 mg po tid).
ALTERNATIVES
TO ACE INHIBITORS: LOSARTAN AND
HYDRALAZINE-ISOSORBIDE
DINITRATE COMBINATION
Recent
studies have shown that
losartan provides similar
but not superior benefit to ACE inhibitors in improved mortality and
reduced
hospitalizations. However, because of the much larger body of data
supporting
their use, ACE inhibitors remain the first line vasodilator. Losartan
should
be prescribed instead of ACE inhibitors only in patients intolerant to
ACE inhibitors because of intractable cough, rash, or angioedema.
Losartan
should be used with caution in patients with a history of angioedema
from
an ACE inhibitor. Angioedema has been reported as a rare adverse
occurrence
with angiotensin II receptor blockers despite the lack of an effect on
bradykinin. Losartan is as likely to produce renal insufficiency and
hyperkalemia
as are ACE inhibitors; therefore, for patients with severe renal
insufficiency
(e.g., creatinine > 3 mg/dL) and hyperkalemia (e.g., potassium
>5.0 - 5.5
mmol/L), hydralazine-isosorbide dinitrate (HYD/ISDN) combination
remains
the alternative vasodilator of choice. In addition, some patients
unable
to tolerate even a low dose of ACE inhibitors due to symptomatic
hypotension
may tolerate hydralazine-isosorbide dinitrate.
Losartan may be
titrated every 1 - 2 weeks beginning at
a dose of 12.5 mg po qd up to 50 mg po qd. In patients with
hypertension,
losartan may be increased to 50 mg po bid. Patients should have blood
pressure,
creatinine, and serum potassium checked within 1 week of initiation and
dosage increases.
BETA-BLOCKERS
In more than 20 trials
involving greater than 10,000
heart failure patients, beta-blockers (carvedilol, metoprolol, and
bisoprolol
[non-formulary]) lengthened survival, improved symptoms, and prevented
hospitalizations. All patients with systolic dysfunction and NYHA class
II - III symptoms should receive a beta-blocker unless they have an
absolute
contraindication or are unable to tolerate the drug.
Contraindications
Absolute contraindications to
beta-blockers include bronchospastic
disease, symptomatic
bradycardia
or advanced heart
block (unless treated with
a pacemaker). Bronchospastic
disease should be
distinguished from wheezing due to
heart failure and from COPD without
bronchospasm, neither of which
should exclude the use
of beta-blockers. A relative
contraindication is
asymptomatic bradycardia (heart rate
< 60 beats/minute). Treatment
should not be initiated in
patients in the midst of an
acute decompensation. The benefits and
safety of beta-blockers in
patients with class IV heart
failure remain uncertain and use in these
patients should be considered
experimental. The ongoing
COPERNICUS trial is evaluating the use
of beta-blockers in class IV
heart failure.
Initiation
of beta-blocker
therapy
Beta-blockers
should be
started after diuretic and ACE
inhibitor doses have been optimized and the patient has remained
clinically
stable for more than two weeks. Start at a low dose (carvedilol
3.125 mg
po bid, metoprolol 6.25 mg susp - 12.5 mg po ql2hr) and double the dose
as the patient tolerates every 2 - 4 weeks to the target dose
(carvedilol
25-50 mg po ql2hr, metoprolol 100 mg po ql2hr).
Choice of agents
Benefits of beta-blockers have
been clearly shown in
large clinical trials of metoprolol, carvedilol,
and bisoprolol. Whether all
beta-blockers are equally
beneficial is unknown. A recently
presented study of bucindolol
showed no benefit for this
agent. Carvedilol and metoprolol are
being compared in the ongoing
COMET study.
Side
effects
If a
patient develops
hypotension, consider
*delaying up-titration of
beta-blocker,
*temporarily
decreasing dose
of ACE inhibitor or vasodilator,
or
*decreasing
diuretic if the
patient is hypovolemic.
After beta-blocker
titration, the dose of vasodilator
usually can be returned to prior dose.
If a patient develops
fluid retention or worsening heart
failure, increase diuretics and consider
delaying up-titration of
beta-blocker. Patients should
be instructed to monitor fluid retention
by weighing themselves daily
and to notify their provider
of a 2 pound weight gain in one day or
5 pounds in one week.
If a patient develops
a heart rate less than 50 beats/min
or second- or third-degree heart block,
rule-out other rate slowing
drugs (e.g., digoxin) and
consider decreasing the dose of beta-blocker.
If a patient develops
wheezing due to bronchospasm and
not due to worsened pulmonary congestion, discontinue the beta-blocker.
If a patient develops
mild to moderate worsening of heart
failure, consider continuing the beta-
blocker while the patient is
stabilized with diuretics.
If the patient experiences a severe decompensation (particularly those
requiring I.V. inotropes or not responding to acute therapy),
consider temporarily reducing
the dose or discontinuing
the beta-blocker.
Patient
counseling
regarding beta-blockers
Patients
should be educated
that early beta-blocker side
effects, including worsened heart failure, are usually treatable and
improve
over time improvement in symptoms may not occur until after 2 - 3
months
of treatment even if no improvement in symptoms occurs, beta-blockers
prevent
disease progression and improve survival.
SPIRONOLACTONE
Recently spironolactone has
been shown to prolong survival,
reduce hospitalizations, and
improve symptoms for patients
with severe (NYHA Class
III or IV) heart failure. Spironolactone (12.5 to 25 mg po daily) may
be
considered for patients who have been maximized on vasodilator therapy
and continue to have NYHA class III or IV symptoms. In order to reduce
the chance of hyperkalemia, avoid adding spironolactone while titrating
ACE inhibitors or losartan.
Initial
dose of
spironolactone is usually 25 mg po per
day. When hyperkalemia or renal
insufficiency is or becomes a
concern, the dose may be
started at or decreased to 12.5 mg. For
patients who tolerate 25 mg
but whose heart failure progresses,
the dose may be increased to
50 mg. However, spironolactone
is a weak diuretic and
should not be titrated to higher
doses in an attempt to replace
loop diuretics.
Contraindications
to
spironolactone:
*Sustained
serum
creatinine > 2.5 mg/dL
*Serum K+ >
5.0 mEq/L
Other
potassium-sparing diuretics and supplementary potassium
should be discontinued when starting spironolactone. Although
well-tolerated,
side effects include hyperkalemia, gynecomastia and/or breast pain in
men.
Serum potassium should be checked at least at baseline, 1,4, and 8
weeks.
INOTROPES
Parenteral inotropic agents
may be considered for hemodynamic
and clinical support of
patients
with decompensated
low-output heart failure
refractory to maximal medical therapy.
Because of lack of
demonstrated benefit and concerns
about toxicity, elective infusion of
positive inotropes cannot be
recommended in any setting.
ANTIARRHYTHMICS
Amiodarone is the only
antiarrhythmic agent that has
been clearly shown not to increase
mortality in patients with
systolic dysfunction. It is
the drug of choice for the treatment of atrial
flutter and fibrillation in
these patients. Patients
should be monitored for side effects including
liver, lung, and thyroid
toxicities. Amiodarone is not
recommended routinely for primary
prevention of sudden death in
patients with left-ventricular
dysfunction.
Class
I
antiarrhythmic agents (e.g., quinidine, procainamide,
flecainide) have increased sudden
death in trials of patients
with left-ventricular dysfunction.
These agents should not be used in
heart failure patients unless
there are no other alternatives.
NSAIDS
Avoid
NSAIDS when possible
(except ASA 325 mg or less,
once daily, when indicated). NSAIDS can inhibit the effects of
diuretics
and ACE inhibitors and can worsen both cardiac and renal function.
OTHER BLOOD PRESSURE
LOWERING DRUGS
If
the use of blood pressure
lowering drugs (e.g., nitrates,
prazosin or clonidine) is limiting the
titration of agents that
prolong survival (e.g., vasodilators,
beta-blockers), consider decreasing
or discontinuing except in
patients on nitrates for ongoing
ischemia or in combination with
hydralazine.
Titrate
dose every 1 - 2 weeks.
Check
creatinine and
potassium 3 - 7
days
after each increase.
LOOP DIURETICS
Furosemide
Burmetanide
10-
40 mg po qd
0.5 mg IV
400 rug po
qd
10 mg
IV qd
Hypotension,
¯K , ¯
Mg, ¯Na, skin rash,
azotemia.
Rare severe
reactions include
pancreatitis,
ototoxicity. bone marrow
suppression,
and
systemic lupus erythematosus
Initiate
loop diuretic in patient with
severe
volume overload.
Avoid
overdiuresis
before
starting ACEI. Monitor potassium
frequently during initiation, titration or modification of diuretic
25 mg po qd
2.5 mg
po (AS A
SINGLE
TEST
DOSE INITIALLY).
MAXIMALLY
EFFECTIVE
WHEN
GIVEN 30
MINUTES
PRIOR
TO FUROSEMIDE
50
mq po qd
10 mg
po qd
Hypokalemia
with metolazone can be dramatic.
Hypotension,
¯K,
¯Mg,
¯Na,
Ca,
hyperlipidemia,
hyperglycemia, hyperuricemia, skin rash,
azotemia. Rare severe reactions include pancreatitis, bone
marrow
suppression, and anaphylaxis.
Initiate
thiazide diuretic in patient with mild
volume
overload. Avoid overdiuresis before starting ACEI.
Monitor
potassium frequently during initiation, titration or modification of
diuretic.
Give
initial dose and any increased doses at
bedtime
with food. Start at a low dose and double the dose as patient
tolerates
2 - 4 weeks to target dose.
OVERVIEW
OF MEDICATION TITRATION IN HEART FAILURE
ACUTE
HEART FAILURE
*Diurese
and
* Optimize
ACE inhibitors
(ACEI) to target dose (lisinopril
20 mg) or to max dose (40 mg) if necessary
to stabilize
*If ACEI not tolerated, use
losartan or hvdralazine/isosorbide
dinitrate
ONCE
STABLE
*
Optimize ACEI to target
dose
*If
class I-III, optimize beta
blocker to target dose, and
if class III or
IV,
add
spironolactone
*ACEI
to max dose (if SBP
> 90)
ONCE
ON OPTIMAL DOSES
OF A FIRST VASODILATOR AND BETA-BLOCKER:
* For patients without
elevated BP, if still symptomatic
on optimal ACEI, beta-blocker, and diuretics:
add digoxin (aim for low
level.about 1.0).
SELECTED
REFERENCES
GENERAL
ACC/AHA task for report.
Guidelines for the evaluation
and management of heart failure.
Report of the American College
of Cardiology/American
Heart Association Task Force on Practice Guidelines
(Committee on
Evaluation and Management of Heart Failure). J Am Coll
1995;26:1376-98
Steering
Committee
and Membership of the Advisory Council
to Improve Outcomes Nationwide in
Heart Failure. Consensus
recommendations for the management
of chronic heart failure. AmerJCardiology
1999;83(2A):1A-38A
ACE
INHIBITORS
CONSENSUS
Trial Study Group.
Effects of enalapril onmortality
in severe congestive heart failure: results of the Cooperative North
Scandinavian
Enalapril Survival Study (CONSENSUS) N Engl J Med 1987;316;1429-35
Packer M.
Poole-Wilson P, Armstrong P, et al. Comparative
effects of low-dose versus high-dose lisinopril on survival and major
events
in chronic heart failure: the Assessment ofTreatment with Lisinopril
and
Survival Study (ATLAS). (Abstr) Eur Heart J 1998;
19(suppl):142.
Packer
M.
Poole-Wilson P, Armstrong PW. et al. on behalf
of the ATLAS Study Group. Comparative
effects of low and high doses
of the anguitensin-converting
enzyme inhibitor lisinopril, on morbidity and mortality in chronic
heart
failure.Circulation 1999;100:2312-18
Pfeffer M. Braunwald E, Moye
L, et al.. for the SAVE Investigators.
Effect of captopril on mortality
and morbidity in
patients with left ventricular dysfunction
after myocardial infarction: results of the Survival and Ventricular
Enlargement
trial..N Engl J Med 1992;327:669-77
SOLVD Investigators.
Effect of enalapril on survival in
patients with reduced left ventricular ejection
fractions and congestive heart
failure. N Engl J Med
1991;325:293-302
SOLVD
Investigators.
Effect of enalapril on mortality
and the development of heart failure in
asymptomatic patients with
reduced left ventricular ejection
fractions.N Engl J Med 1992;327:685-91
ANGIOTENSIN
IIRECEPTOR BLOCKERS
Pitt
B. Segal R. Maitinez FA,
et al. Randomized trial
of losartan versus captopril in patients over 65 with
heart failure (Evaluation of
Losartan in the
Elderly
Study. ELITE).Lancet
1997;349:747-52
Tsuyuki
RT,. Yusuf S.
Rouleau JL et al. Combination neurohormonal
versus blockade with ACE
inhibitors,
angiotensin II
antagonists and beta-blockers
in patients with congestive heart failure:
design of the randomized
evaluation of strategies for
left ventricular dysfunction
(RESOLVD) pilot study. Can
J Cardiol 1997;13:1166-74.
HYDRALAZINE-ISOSORBIDE
DINITRATE COMBINATION
Cohn JN, .Archibald
DG, Zieche S. el al. Effect of vasodilator
therapy on mortality in chronic
congestive heart failure
(VHeFt I). N Engl JMed
1986;314:1547-52.
Cohn
JN, Johnson G,
Ziesche S, et al. A comparison of
enalapril rith
hvdralazine-isosorbide dinitrate in the
treatment of chronic congestive heart
failure (VHeFt II).N
Engl J Med 1991;325:303-10
BETA - BLOCKERS
Australia/New Zealand Heart
Failure Research Collaborative
Group. Randomized. placebo-
controlled
trial of carvedilol
in patients with congestive
heart failure due to ischaemic heart
disease. Lancet
1997;349:375-80.
CIBIS
Investigators
and Committees. A randomized trial
of beta-blockade in heart failure: the
Cardiac Insufficiency
Bisoprolol Study- (CIBIS). Circulation
1994;90:1765-73.
CIBIS
Invdestigators
and Committees. The Cardiac Insufficiency
Bisoprolol Study II (CIBIS-II): a
randomised trial. Lancet
1999;353:9-13
Colucci
WS. Packer M. Bristow
MR, et al., for the US Carvedilol
Heart Failure Study Group. Carvedilol
inhibits clinical progression
in patients with mild symptoms
of heart failure. Circulation 1996;94:2800-6
MERIT-HF
Investigators. Effect of metoprolol CR/XL in
chronic heart failure: Metoprolol CR/XL
Randomised Intervention Trial
in Congestive Heart Failure
(MERIT-HF). Lancet 1999;353:2001-7
Packer M, Bristow MR,
Cohn JN, et al. The effect of carvedilol
on morbidity and mortality in patients
with congestive heart failure.
N Engl J
Med 1996;334:1349-55
Packer M. Colucci WS,
Sackner-Bernstein JD, et al. Double-blind,
placebo-controlled study of the
effects of carvedilol in
patients with moderate to severe
heart failure. The PRECISE Trial.
Prospective Randomized
Evaluation of Carvedilol on Symptoms
and Exercise. Circulation
1996;94:2793-9.
Sanderson JE, Chan
SK, Yip G, et al. Beta-blockade in
heart failure: a comparison of carvedilol with
metoprolol. J Am
Coll Cardiol 1999;34:1522-8.
Tsuyuki RT, Yusuf S.
Rouleau JL et al. Combination neurohormonal
blockade with ACE inhibitors.
angiotensin II antaeonists,
and beta-b!ockers in patients
with congestive heart failure: design of
the Randomized Equation of
Strategies for Left Ventricular
Dysfunction (RESOLVD) Pilot Study.
Can J Cardiol
1997;13:1166-1174.
White M, Rouleau , JL
Pericak D, et al, on behalf of the
RESOLVD) Study Group. Effects of metoprolol-CR
in patients with ischaemic and
dilated cardiomyopathy:
the RESOLVD pilot study (phase II). (Abstr.) Eur Heart J
1998:19(suppl):308
REFERENCES
SPIRONOLACTONE
Pitt B, Zannad F, Remme WJ, et
al. for the Randomized
Aldactone
Evalualion Study
Investigators. The effect
of
spironolactone
on mortildity
and mortality in patients
with
severe heart failure. N
Engl J. Med 1999;3441:709-717
INOTROPES
Elis A, Bental T, Kimchi 0, el
al. Intermittent dobutamine
treatment in patients with chronic refractory
congestive heart failure: a
randomized, double-blind,
placebo controlled study. Clin PharmacolTher
1998;63:682-5
Packer M. Carver J,
Rodeheffer R, et al. Effect of oral
milrinone on mortality in
severe chronic heart failure. N
Engl J Med 1991;325:1468-75
AMIODARONE
Doval HC, Nul DR, Grancelli
HO, et al. Randomized trial
of
low dose
amiodarone in severe
congestive heart failure. Lancet
1994;344:493-8.
Massie
BM, Fisher SG,
Radford M, et al. Effect of amiodarone
on clinical status and left ventricular
function in patients with
congenital heart failure. CHF-STAT
Investigators. Circulation
1996;93:2128-34.
Sineh S. Fletcher R,
Fisher S, et al. Amiodarone in patients
with congestive heart failure
and asymptomatic
ventricular
arrhythmia.N
Engl J Med 1995;333:77-82
DIGOXIN
Digitalis Investigation Group.
The effect of digoxin
on
mortality and
morbidity in
patients w.h heart failure. N
Engl J Med 1997;336:525-33
CALCIUM CHANNEl
BIOCKERS
Cohn J,
Ziesche S, Smith R, et
al. Effect of calcium
antagonist felodipine as supplementary vasodilalor
therapy in patients with
chronic heart failure treated
with enalapril. V-HeFT III. Circulation 1997;96:856-63.
MullerJE, MorrisonJ,
Stone PH, et al. Nifedipine therapy
for patients with threatened and acute myocaridal
infarction: a randomized,
double-blind, placebo-controled
comparison. Circulation 1984;69:740-7.
O'Connor CM, Carson
PE, Miller AB, et al. Effect of amlodipine
on mode of death among patients with
advanced heart failure in the
PRAISE trial. Prospective
Randomized Amiodipine Survival Evaluation. Am J
Cardiol 1998;82:881-7
Packer M, O'Connor C,
Ghali J, et al. Effect of amiodipine
on
morbidity and
mortality in
severe chronic heart failure
(PRAISE). N Engl J Med 1996;335:1107-14.
ACKNOWLEDGMENTS
Clinical Leaders
Anthony Steimie, MD;
Cardiology, Santa Clara
Jonathan
Allen, MD;
Cardiology, Walnut Creek
Project
Management
Julie
Lenhart. RPh, MS: TPMG
Department of Quality &
Utilization
David
St. Pierre. MHROD: TPMG
Department of Quality &
Utilization
Data
Analysis
Victoria
Travis. MS; TPMG
Dept. of Quality & Utilization
Nicole Morin; TPMG Dept of
Quality & Utilization
Betsy Stone. DrPH: TPMG DepL
of Quality & Utilization
Reviewers
Robert S. Blumberg, MD;
Cardiology, Redwood City
Tim
Corfman, MD; Medicine,
Walnut Creek
Paul
Feigenbaum, MD; Medicine,
San Francisco
Thad
Foster, MD; Medicine,
Roseville
David
Gee, MD; Cardiology,
Walnut Creek
Robert
Goldfien, MD; Medicine,
Richmond
David
Judge, MD; Cardiology,
San Rafael
Arthur
L Klatsky, MD;
Cardiology, Oakland
David
Langkammer, MD;
Medicine, Antioch
Stanley
Nussbaum, MD;
Cardiology/Family Medicine, Santa
Rosa
Donald A.
Pierce, MD;
Medicine. Novato
Cathlene
Richmond, PharmD;
Pharmacy, Divisional Offices
Jeff Ritterman, MD; Medicine,
Richmond
Paul
Rose, DO; Medicine,
Stockton
Ralph
J. Wessel, MD;
Cardiology, Fresno
David
Williams, MD;
Cardiology, Vallejo
Kaiser
Permanente
Northern California
TPMG
Department of Quality and
Utilization
1800
Harrison Street, 4th Floor
Oakland.
CA 94612
510-987-2950
or tie-line
8-427-2950
To
obtain more
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Guidelines, printed copies or permission to reproduce
any portion, please contact
the TPMG Dept. of Quality
& Utilization. or send an e-mail message to
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KPNC Clinical Practice
Guidelines can be viewed on-line
on the Kaiser Permanente Northern California intranet at
http://cl.kp.org
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Disclaimer
The Permanente Medical
Group TPMG Clinical Practice
Guidelines have been developed to assist
clinicians by providing an
analytical framerork for the
evaluation and treatment of selected common problems
encountered in patients. These
guidelines are not intended
to establish a protocol for all patients with a
particular condition. While
the guidelines provide one
approach to evaluating a problem, clinicial conditions
may vary significantly from
individual to individual.
Therefore, the clinician must exercise independent
judgment and make decisions
based upon the situation
presented.While great care has been taken to assure the
accuracy of the information
presented, the reader is
advised that TPMG cannot be responsible for continued
currency of the information,
for any errors or omissions
in this guidelines, or for any consequences arising from its use.
